Version 1
: Received: 14 September 2023 / Approved: 15 September 2023 / Online: 20 September 2023 (07:48:05 CEST)
How to cite:
Avinery, L.; Regev, D.; Khamaisi, H.; Gopas, J.; Mahajna, J. Hypoxic Conditions Confer Chemoresistance to Crizotinib but not to Imatinib in Chronic Myeloid Leukemia (CML) Cells Depending on HIF1α and JAK2. Preprints2023, 2023091245. https://doi.org/10.20944/preprints202309.1245.v1
Avinery, L.; Regev, D.; Khamaisi, H.; Gopas, J.; Mahajna, J. Hypoxic Conditions Confer Chemoresistance to Crizotinib but not to Imatinib in Chronic Myeloid Leukemia (CML) Cells Depending on HIF1α and JAK2. Preprints 2023, 2023091245. https://doi.org/10.20944/preprints202309.1245.v1
Avinery, L.; Regev, D.; Khamaisi, H.; Gopas, J.; Mahajna, J. Hypoxic Conditions Confer Chemoresistance to Crizotinib but not to Imatinib in Chronic Myeloid Leukemia (CML) Cells Depending on HIF1α and JAK2. Preprints2023, 2023091245. https://doi.org/10.20944/preprints202309.1245.v1
APA Style
Avinery, L., Regev, D., Khamaisi, H., Gopas, J., & Mahajna, J. (2023). Hypoxic Conditions Confer Chemoresistance to Crizotinib but not to Imatinib in Chronic Myeloid Leukemia (CML) Cells Depending on HIF1α and JAK2. Preprints. https://doi.org/10.20944/preprints202309.1245.v1
Chicago/Turabian Style
Avinery, L., Jacob Gopas and Jamal Mahajna. 2023 "Hypoxic Conditions Confer Chemoresistance to Crizotinib but not to Imatinib in Chronic Myeloid Leukemia (CML) Cells Depending on HIF1α and JAK2" Preprints. https://doi.org/10.20944/preprints202309.1245.v1
Abstract
Chronic myeloid leukemia (CML) is the most common form of leukemia in adults and accounts for approximately 15% of all leukemia cases. The etiology of this disease is based on the presence of the oncogenic Bcr/Abl fusion protein, which has dysregulated tyrosine kinase activity. This pathological condition is the result of a chromosomal translocation between chromosomes 9 and 22 leading to the formation of the Philadelphia chromosome (Ph). Clinical establishment of targeted therapy with Abl kinase inhibitors (AKIs) has been observed in the treatment of CML. Therapy resistance in patients with CML is due to genetic alterations in the cells of CML, specifically affecting the Bcr/Abl oncoprotein. Acquired resistance of CML patients to tyrosine kinase inhibitors (AKIs) has also been associated with the tumor microenvironment (TME). This study aimed to examine the role of hypoxic conditions in the development of chemoresistance to certain AKIs in CML. The findings of our study indicate that exposure to hypoxic conditions leads to a substantial increase in chemoresistance to crizotinib, while only resulting in a slight increase in chemoresistance to imatinib. It is worth noting that both drugs effectively block Bcr/Abl function. Furthermore, it was observed that the inclusion of the JAK1/2 inhibitor ruxolitinib resulted in an augmentation of chemoresistance to crizotinib in the context of hypoxia. Overexpression of hypoxia-inducible factor 1a (HIF1a) and silencing of JAK2 confirmed that the two proteins cooperate in mediating chemoresistance to crizotinib in CML cell lines. It is noteworthy that the compound 2-methoxy estradiol (2ME2), which is a metabolite of estradiol lacking estrogenic activity, has shown efficacy in reinstating the sensitivity of CML cells to crizotinib in the presence of hypoxic circumstances. Additionally, when used in conjunction with a JAK2 inhibitor, 2ME2 exhibited activity in restoring crizotinib sensitivity in CML cells. The findings of our study underscore the significance of selectively targeting elements of the HIF1α pathway in order to achieve total eradication of chronic myeloid leukemia (CML) cells.
Biology and Life Sciences, Biochemistry and Molecular Biology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
